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Mercury-induced apoptosis and necrosis in murine macrophages: role of calcium-induced reactive oxygen species and p38 mitogen-activated protein kinase signaling.
Toxicol Appl Pharmacol. 2004 Apr 01; 196(1):47-57.TA

Abstract

The current study characterizes the mechanism by which mercury, a toxic metal, induces death in murine macrophages. The cytotoxic EC(50) of mercury ranged from 62.7 to 81.1 microM by various assays in J774A.1 cultures; accordingly, we employed 70 microM of mercuric chloride in most experiments. Mercury-induced intracellular calcium modulated reactive oxygen species (ROS) production, which resulted in both cell apoptosis and necrosis indicated by annexin V binding and caspase-3 activity, and propidium-iodide binding. Calcium antagonists abolished ROS production. Mercury stimulated p38 mitogen-activated protein kinase (MAPK) and additively stimulated lipopolysaccharide-activated p38. Mercury-activated p38 was decreased by pretreatment of cells with antioxidants, N-acetylcysteine (NAC) and silymarin, indicating that mercury-induced ROS were involved in p38 activation. Mercury increased the expression of tumor necrosis factor alpha (TNFalpha); antioxidants and a specific p38 inhibitor decreased this effect. Pretreatment with antioxidants, p38 inhibitor, and anti-TNFalpha antibody decreased mercury-induced necrosis; however, anti-TNFalpha antibody did not decrease mercury-induced apoptosis. Results suggest that mercury-induced macrophage death is a mix of apoptosis and necrosis employing different pathways. P38-mediated caspase activation regulates mercury-induced apoptosis and p38-mediated TNFalpha regulates necrosis in these cells. Calcium regulates ROS production and mercury-induced ROS modulate downstream p38 that regulates both apoptosis and necrosis.

Authors+Show Affiliations

Interdisciplinary Program in Toxicology, Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15050407

Citation

Kim, Sang Hyun, and Raghubir P. Sharma. "Mercury-induced Apoptosis and Necrosis in Murine Macrophages: Role of Calcium-induced Reactive Oxygen Species and P38 Mitogen-activated Protein Kinase Signaling." Toxicology and Applied Pharmacology, vol. 196, no. 1, 2004, pp. 47-57.
Kim SH, Sharma RP. Mercury-induced apoptosis and necrosis in murine macrophages: role of calcium-induced reactive oxygen species and p38 mitogen-activated protein kinase signaling. Toxicol Appl Pharmacol. 2004;196(1):47-57.
Kim, S. H., & Sharma, R. P. (2004). Mercury-induced apoptosis and necrosis in murine macrophages: role of calcium-induced reactive oxygen species and p38 mitogen-activated protein kinase signaling. Toxicology and Applied Pharmacology, 196(1), 47-57.
Kim SH, Sharma RP. Mercury-induced Apoptosis and Necrosis in Murine Macrophages: Role of Calcium-induced Reactive Oxygen Species and P38 Mitogen-activated Protein Kinase Signaling. Toxicol Appl Pharmacol. 2004 Apr 1;196(1):47-57. PubMed PMID: 15050407.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mercury-induced apoptosis and necrosis in murine macrophages: role of calcium-induced reactive oxygen species and p38 mitogen-activated protein kinase signaling. AU - Kim,Sang Hyun, AU - Sharma,Raghubir P, PY - 2003/09/16/received PY - 2003/11/24/accepted PY - 2004/3/31/pubmed PY - 2004/5/5/medline PY - 2004/3/31/entrez SP - 47 EP - 57 JF - Toxicology and applied pharmacology JO - Toxicol Appl Pharmacol VL - 196 IS - 1 N2 - The current study characterizes the mechanism by which mercury, a toxic metal, induces death in murine macrophages. The cytotoxic EC(50) of mercury ranged from 62.7 to 81.1 microM by various assays in J774A.1 cultures; accordingly, we employed 70 microM of mercuric chloride in most experiments. Mercury-induced intracellular calcium modulated reactive oxygen species (ROS) production, which resulted in both cell apoptosis and necrosis indicated by annexin V binding and caspase-3 activity, and propidium-iodide binding. Calcium antagonists abolished ROS production. Mercury stimulated p38 mitogen-activated protein kinase (MAPK) and additively stimulated lipopolysaccharide-activated p38. Mercury-activated p38 was decreased by pretreatment of cells with antioxidants, N-acetylcysteine (NAC) and silymarin, indicating that mercury-induced ROS were involved in p38 activation. Mercury increased the expression of tumor necrosis factor alpha (TNFalpha); antioxidants and a specific p38 inhibitor decreased this effect. Pretreatment with antioxidants, p38 inhibitor, and anti-TNFalpha antibody decreased mercury-induced necrosis; however, anti-TNFalpha antibody did not decrease mercury-induced apoptosis. Results suggest that mercury-induced macrophage death is a mix of apoptosis and necrosis employing different pathways. P38-mediated caspase activation regulates mercury-induced apoptosis and p38-mediated TNFalpha regulates necrosis in these cells. Calcium regulates ROS production and mercury-induced ROS modulate downstream p38 that regulates both apoptosis and necrosis. SN - 0041-008X UR - https://www.unboundmedicine.com/medline/citation/15050407/Mercury_induced_apoptosis_and_necrosis_in_murine_macrophages:_role_of_calcium_induced_reactive_oxygen_species_and_p38_mitogen_activated_protein_kinase_signaling_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041008X03005544 DB - PRIME DP - Unbound Medicine ER -